JP2010513223A - N-hydroxyacrylamide compounds - Google Patents

Abstract

（式中、Ｒ¹は水素、置換されてもよい低級アルキル、シクロ（低級）アルキル、シクロ（高級）アルキル、置換されてもよいアリール、置換されてもよいヘテロサイクリル、またはアリール縮合シクロ（低級）アルキルであり、
Ｒ²は水素またはハロゲンであり、ＺはＣＨまたはＮであり、
Ｘは式（ＩＩ）：

であり、Ｒ³は−ＯＨもしくは置換されてもよいアリールで置換されてもよい低級アルキル、または低級アルカノイルであり、
Ｒ⁴は水素または低級アルキルであり、
Ｙは置換されてもよい低級アルキレンである）
を有する化合物またはその塩。該化合物はヒストンデアセチラーゼ阻害剤として有用である。The following formula (I):

Wherein R ¹ is hydrogen, optionally substituted lower alkyl, cyclo (lower) alkyl, cyclo (higher) alkyl, optionally substituted aryl, optionally substituted heterocyclyl, or aryl fused cyclo ( Lower) alkyl,
R ² is hydrogen or halogen, Z is CH or N,
X is the formula (II):

R ³ is —OH or lower alkyl optionally substituted with optionally substituted aryl, or lower alkanoyl;
R ⁴ is hydrogen or lower alkyl,
Y is optionally substituted lower alkylene)
Or a salt thereof. The compounds are useful as histone deacetylase inhibitors.

Description

  The present invention relates to a compound useful as a pharmaceutical, and a pharmaceutical composition containing the same.

  Histone deacetylase (hereinafter also referred to as “HDAC”) is known to play an important role in the transcriptional mechanism for regulating gene expression, induce histone hyperacetylation, and affect gene expression. ing. Thus, such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukemia (APL), organ transplant rejection, autoimmune diseases, protozoal infections, tumors, It is useful as a therapeutic or prophylactic agent for diseases caused by abnormal gene expression.

  Many compounds (HDAC inhibitors) that can inhibit the function of the enzyme have been extensively studied (eg, International Publication No. WO 2004/024160, US Patent No. 2004/087631, International Publication No. WO 2004 / No. 063169, US Patent No. 2004/092558, International Publication No. WO2005 / 086898, International Publication No. WO2006 / 016680, International Publication No. WO2006 / 102760, International Publication No. WO2006 / 105979, International Publication No. WO 2006/117548, International Publication No. WO 2006/122319, etc.).

（式中
Ｃｙは、それぞれが置換されてもよいシクロアルキル、アリール、ヘテロアリールまたはヘテロサイクリルであり；
Ｌ¹は、ｍが０から４の整数であり、Ｗが−Ｃ（Ｏ）ＮＨ−、−Ｓ（Ｏ）₂ＮＨ−などからなる群から選択される−（ＣＨ₂）_m−Ｗ−であり；
Ａｒは、置換されてもよいアリーレンであって、アリール、ヘテロアリール環などと縮合していてもよく；
Ｙ¹は、化学結合または直鎖もしくは分岐鎖飽和アルキレンであり、ここで前記アルキレンは置換されてもよく；ならびに
Ｚは、アニリニル、ピリジル、チアジアゾリル、およびＭがＨまたは医薬的に許容される陽イオンである−Ｏ−Ｍからなる群から選択される。 For example, International Publication No. WO 01/38322 discloses histone deacetylase inhibitors represented by the following formula:

Wherein Cy is cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which may be substituted;
L ¹ is an integer from 0 to 4, and W is — (CH ₂ ) _m —W—, wherein W is selected from the group consisting of —C (O) NH—, —S (O) ₂ NH—, and the like. Yes;
Ar is an optionally substituted arylene and may be fused with an aryl, heteroaryl ring, etc .;
Y ¹ is a chemical bond or a linear or branched saturated alkylene, wherein said alkylene may be substituted; and Z is anilinyl, pyridyl, thiadiazolyl, and M is H or a pharmaceutically acceptable positive It is selected from the group consisting of -OM which is an ion.

（式中
Ｒ₁は、Ｈ、ハロまたは直鎖Ｃ₁〜Ｃ₆アルキルであり；
Ｒ₂は、Ｈ、Ｃ₁〜Ｃ₁₀アルキル、Ｃ₄〜Ｃ₉シクロアルキル、Ｃ₄〜Ｃ₉ヘテロシクロアルキル、Ｃ₄〜Ｃ₉ヘテロシクロアルキルアルキル、シクロアルキルアルキル、アリール、ヘテロアリールなどから選択され；
Ｒ₃およびＲ₄は、同一または異なっておよび独立して、Ｈ、Ｃ₁〜Ｃ₆アルキル、アシルもしくはアシルアミノであるか、または
Ｒ₃およびＲ₄は、それらが結合している炭素と一緒になってＣ＝Ｏ、Ｃ＝Ｓなどを表すか、または
Ｒ₂はその結合している窒素と一緒になっておよびＲ₃はその結合している炭素と一緒になって、Ｃ₄〜Ｃ₉ヘテロシクロアルキル、ヘテロアリール、ポリへテロアリール、非芳香性ポリヘテロサイクル、または芳香性および非芳香性混合ポリヘテロサイクル環を形成し；
Ｒ₅は、Ｈ、Ｃ₁〜Ｃ₆アルキルなどから選択され；
ｎ、ｎ₁、ｎ₂およびｎ₃は、同一または異なっておよび独立して０〜６から選択され、ｎ₁が１〜６であるとき各炭素原子は任意におよび独立してＲ₃および／またはＲ₄で置換されることができ；
ＸおよびＹは、同一または異なっておよび独立して、Ｈ、ハロ、Ｃ₁〜Ｃ₄アルキルなどから選択される）
またはその医薬的に許容される塩を開示する。 International Publication No. WO 02/22577 describes the following hydroxamate compounds as deacetylase inhibitors:

Wherein R ₁ is H, halo or straight chain C ₁ -C ₆ alkyl;
R ₂ is, H, C ₁ -C ₁₀ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, C ₄ -C ₉ heterocycloalkyl, cycloalkylalkyl, aryl, etc. heteroaryl Selected;
R ₃ and R ₄ are the same or different and independently H, C ₁ -C ₆ alkyl, acyl or acylamino, or R ₃ and R ₄ together with the carbon to which they are attached. C = O, C = S, etc., or R ₂ together with its attached nitrogen and R ₃ together with its attached carbon, C ₄ -C ₉ Forming a heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle, or mixed aromatic and non-aromatic polyheterocycle rings;
R ₅ is selected from H, C ₁ -C ₆ alkyl and the like;
n, n ₁ , n ₂ and n ₃ are the same or different and independently selected from 0-6, and when n ₁ is 1-6, each carbon atom is optionally and independently R ₃ and / or Or can be substituted with R ₄ ;
X and Y are the same or different and independently, H, halo, etc. C ₁ -C ₄ alkyl)
Or a pharmaceutically acceptable salt thereof.

  The present invention relates to a novel compound useful as a medicament and a pharmaceutical composition containing the same.

  More particularly, the present invention relates to compounds having a potent inhibitory effect on the activity of histone deacetylases.

  The inventors of the present invention have also found that histone deacetylase inhibitors such as compounds of formula (I) (hereinafter referred to as compound (I)) have a strong immunosuppressive effect and a strong antitumor effect. It was. Accordingly, histone deacetylase inhibitors such as compound (I) are useful as active ingredients for immunosuppressive and anti-tumor agents, as well as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemias, fibrosis It is useful as an active ingredient for treatment or prevention for diseases such as symptom, cirrhosis, acute promyelocytic leukemia (APL), organ transplant rejection, autoimmune disease, protozoan infection, tumor and the like.

  Accordingly, one object of the present invention is to provide a compound having biological activity for treating or preventing the above-mentioned diseases.

  A further object of the present invention is to provide a pharmaceutical composition comprising compound (I) as an active ingredient.

  A further object of the present invention is to provide the use of a histone deacetylase inhibitor such as compound (I) for the treatment or prevention of the diseases as described above.

  A further object of the present invention is to provide a pharmaceutical composition comprising compound (I), and documents relating thereto, which can be used to treat or prevent diseases as described above. Or providing a commercial package that states that it should be used).

（式中
Ｒ¹は水素、置換されてもよい低級アルキル、シクロ（低級）アルキル、シクロ（高級）アルキル、置換されてもよいアリール、置換されてもよいヘテロサイクリル、またはアリール縮合シクロ（低級）アルキルであり、
Ｒ²は水素またはハロゲンであり、
ＺはＣＨまたはＮであり、
Ｘは

であり、
Ｒ³は−ＯＨもしくは置換されてもよいアリールで置換されてもよい低級アルキル、または低級アルカノイルであり、
Ｒ⁴は水素または低級アルキルであり、
Ｙは置換されてもよいアルキレンである）
を有する化合物またはその塩を提供する。 Accordingly, the present invention provides the following formula (I):

Wherein R ¹ is hydrogen, optionally substituted lower alkyl, cyclo (lower) alkyl, cyclo (higher) alkyl, optionally substituted aryl, optionally substituted heterocyclyl, or aryl-fused cyclo (lower ) Alkyl,
R ² is hydrogen or halogen;
Z is CH or N;
X is

And
R ³ is -OH or lower alkyl optionally substituted with optionally substituted aryl, or lower alkanoyl;
R ⁴ is hydrogen or lower alkyl,
Y is an optionally substituted alkylene)
Or a salt thereof.

  The above-mentioned compound or a salt thereof can be prepared by a method as shown in the following reaction formula, or a method disclosed in Production Examples or Examples.

  In the foregoing and following description of the present specification, suitable examples and explanations of the various definitions that the invention intends to fall within the scope are described in detail below.

  Compound (I) of the present invention can be obtained from compound (A) according to, for example, the following methods or the methods disclosed in the Examples.

（式中Ｒ¹、Ｒ²、Ｘ、ＹおよびＺはそれぞれ上記に定義され、Ｒ⁵はヒドロキシ保護基である。） (Method 1)

(Wherein R ¹ , R ² , X, Y and Z are each defined above and R ⁵ is a hydroxy protecting group.)

(Method 1)
Compound (I) can be obtained by subjecting compound (A) to an elimination reaction of a hydroxy protecting group in the presence of an acid.

  The acid includes a hydrogen chloride solution (eg, hydrogen chloride in a solvent such as methanol, dioxane, ethyl acetate, diethyl ether, etc.), acetic acid, p-toluenesulfonic acid, boric acid, and the like.

  Optionally, one or more suitable deprotecting solvents may be used. Such solvents include methanol, ethanol, ethyl acetate, dioxane, diethyl ether, acetic acid and the like.

  The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

  Compound (I) may be a salt, which is also included in the scope of the present invention. For example, when a basic group such as an amino group is present in the molecule, the salt may be an acid addition salt (for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, Benzenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid (eg, [(1S, 4R) -7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl] methanesulfonic acid or The enantiomers thereof), fumaric acid, maleic acid, mandelic acid, citric acid, salicylic acid, salts with organic acids such as malonic acid, glutaric acid, succinic acid, etc.) and acidic groups such as carboxyl groups When a salt is present, a salt is a basic salt (such as a salt with a metal such as lithium, sodium, potassium, calcium, magnesium, aluminum, lysine, etc. Salts with amino acids) are exemplified by such.

  Furthermore, solvates (eg, hydrates, ethanolates, etc.), anhydrides and other polymorphs, or pharmaceutically acceptable salts of Compound (I) are also encompassed within the scope of the present invention.

  When compound (I) has stereoisomerism based on asymmetric carbon atoms or double bonds such as optically active forms, geometric isomers and the like, such isomers and mixtures thereof are also included in the scope of the present invention. The

It should also be noted that pharmaceutically acceptable prodrugs of Compound (I) are within the scope of the present invention. A pharmaceutically acceptable prodrug means a compound having a functional group that can be converted to —COOH, —NH ₂ , —OH or the like under physiological conditions to form the compound (I) of the present invention. .

  In the foregoing and following description of the present specification, suitable examples and explanations of the various definitions that the invention intends to fall within the scope are described in detail below.

  “Halogen” means fluorine, chlorine, bromine and iodine.

“Lower” is intended to mean 1 to 6 carbon atoms “C ₁ -C ₆ ” unless otherwise indicated.

  “Higher” is intended to mean 7 to 11 carbon atoms unless otherwise indicated.

  Suitable “one or more” may include numbers from 1 to 6, preferably from 1 to 3.

  Suitable “lower alkyl” and “lower alkyl” moieties are 1 to 6 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, and the like. It may include straight-chain or branched alkyl having 1 carbon atom.

  Suitable “cyclo (lower) alkyl” and “cyclo (lower) alkyl” moieties may include cycloalkyls having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

  Suitable “cyclo (higher) alkyl” and “cyclo (higher) alkyl” moieties may include cycloalkyls having from 7 to 11 carbon atoms, such as cycloheptyl, cyclooctyl, adamantyl and the like.

  Suitable "lower alkylene" is methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylmethylene, propylmethylene, isopropylmethylene, butylmethylene, isobutylmethylene, propylene, ethylethylene, 1,2- Linear or branched alkylene having 1 to 6 carbon atoms such as dimethylethylene and 1,1,2,2-tetramethylethylene may be included.

Suitable “aryl” or “ar” moieties may include C ₆ -C ₁₆ aryl such as phenyl, naphthyl, anthryl, pyrenyl, phenanthryl, azulenyl, and the “aryl” or “ar” moiety is halogen and heterocyclyl. It may be substituted with one or more substituents selected from the group consisting of ru (lower) alkyl.

Preferred “ar (lower) alkyl” is phenyl (C ₁ -C ₆ ) alkyl such as benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylhexyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, naphthylpentyl, naphthyl naphthyl, such as hexyl (C ₁ ~C ₆₎ may include alkyl.

  Preferred “lower alkoxy” and “lower alkoxy” moieties are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, neopentyloxy, hexyloxy, It may also include straight or branched alkoxy having 1 to 6 carbon atoms such as isohexyloxy.

Preferred “ar (lower) alkoxy” are phenyl (C ₁ -C ₆ ) alkoxy such as benzyloxy, phenethyloxy, phenylpropoxy, phenylbutoxy, phenylhexyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy, naphthylbutoxy, naphthyl It may contain naphthyl (C ₁ -C ₆ ) alkoxy such as pentyloxy and naphthylhexyloxy.

  Suitable “aryl fused cyclo (lower) alkyl” and “aryl fused cyclo (lower) alkyl” moieties include aryl fused cycloalkyls having from 8 to 12 carbon atoms, such as tetrahydronaphthyl, indanyl, benzocyclobutanyl and the like. But you can.

  Suitable “lower alkanoyl” are formyl, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, tert-pentylcarbonyl, neopentylcarbonyl, and the like. In which the alkyl moiety is an alkanoyl which is a straight-chain or branched alkyl having 1 to 5 carbon atoms.

  Preferred “lower alkyl mono- or di-substituted carbamoyl” is carbamoyl; N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-tert- N- (lower) alkylcarbamoyl wherein the alkyl moiety is alkyl having 1 to 6 carbon atoms, such as butylcarbamoyl, N-pentylcarbamoyl, N-neopentylcarbamoyl, N-isopentylcarbamoyl, N-hexylcarbamoyl; N , N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, N, N-diisobutylcarbamoyl, N, N-di-tert-butylcarbamoyl, N, N- Dipentyl Rubamoyl, N, N-dineopentylcarbamoyl, N, N-diisopentylcarbamoyl, N, N-dihexylcarbamoyl, N-ethyl-N-methylcarbamoyl, N-methyl-N-propylcarbamoyl, N-butyl-N -N, N-di (lower) alkylcarbamoyl, wherein the alkyl moiety is an alkyl having 1 to 6 carbon atoms each, such as -methylcarbamoyl, N-methyl-N-isobutylcarbamoyl. Each of these carbamoyls may be substituted with one or more suitable substituents.

  Suitable “suitable substituents” may include lower alkyl, aryl, cyclo (lower) alkyl, and the like.

  Suitable examples of “heteroaryl” and “heteroaryl” moieties include, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (eg, 4H-1,2,4-triazolyl, 1H -1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (for example, 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc .; It may contain an 8-membered (more preferably 5- or 6-membered) heteromonocyclic group.

Suitable examples of “heterocyclyl” or “heterocyclyl” moieties are saturated 3 to 8 members (more preferably 5 or 5 6-membered) heteromonocyclic group;
May contain saturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as morpholino;
As well as the “heterocyclyl” or “heterocyclyl” moiety may be substituted by one or more lower alkyls.

Suitable “hydroxy protecting groups” are as follows:
Lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), preferably methyl;
Lower alkoxy (lower) alkyl (such as methoxymethyl);
Lower alkoxy (lower) alkoxy (lower) alkyl (for example, 2-methoxyethoxymethyl and the like);
Ar (lower) alkyl (eg benzyl (Bn), p-methoxybenzyl, m, p-dimethoxybenzyl, etc.), wherein the aryl moiety may be substituted with one or more suitable substituents, preferably benzyl;
Ar (lower) alkoxy (lower) alkyl (eg benzyloxymethyl, p-methoxybenzyloxymethyl, etc.) wherein the aryl moiety may be substituted with one or more suitable substituents;
(Lower) alkylthio (lower) alkyl (such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), preferably methylthiomethyl;
Tri (lower) alkylsilyl (for example, trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyldimethylsilyl, tri-tert-butylsilyl, etc.), lower alkyldiarylsilyl (for example, methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert- Tri-substituted silyls such as butyldiphenylsilyl (TBDPS), preferably tert-butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl;
A heterocyclic group (eg, tetrahydropyranyl, etc.);
Acyl as shown below [for example, aliphatic acyl such as lower alkanoyl (eg, acetyl, propanoyl, pivaloyl, etc.); aromatic acyl (eg, benzoyl (Bz), toluoyl, naphthoyl, fluorenylcarbonyl, etc.);
Lower alkoxycarbonyl (such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.);
An ar (lower) alkoxycarbonyl (eg, benzyloxycarbonyl, bromobenzyloxycarbonyl, etc.) in which the aryl moiety may be substituted with one or more suitable substituents;
Lower alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.);
Lower alkoxysulfonyl (eg, methoxysulfonyl, ethoxysulfonyl, etc.);
Al (lower) alkanoyl (eg phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, naphthylisobutanoyl, naphthylpentanoyl , Naphthylhexanoyl, etc.);
Al (lower) alkenoyl such as al (C ₃ -C ₆ ) alkenoyl (eg phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, naphthylpropenoyl, naphthylbutenoyl, naphthylmethacryloyl) , Naphthylpentenoyl, naphthylhexenoyl, etc.)];
Lower alkenyl (eg, vinyl, allyl, etc.);

  Preferred hydroxy protecting groups for the present invention are, for example, tetrahydropyranyl, trimethylsilyl, t-butyldimethylsilyl and the like.

  A preferred embodiment of the present invention is shown as follows.

（２）Ｒ¹は水素、低級アルキル、シクロ（低級）アルキル（低級）アルキル、シクロ（高級）アルキル（低級）アルキル、置換されてもよいアル（低級）アルキル、ヘテロアリール（低級）アルキル、シクロ（低級）アルキル、シクロ（高級）アルキル、置換されてもよいアリール、低級アルキルヘテロサイクリル、アリール縮合シクロ（低級）アルキルであり、好ましくは、Ｒ¹はシクロ（低級）アルキル（低級）アルキル、ハロゲン置換されてもよいアル（低級）アルキル、シクロ（低級）アルキル、シクロ（高級）アルキル、またはハロゲン置換されてもよいアリールであり、より好ましくは、Ｒ¹はシクロヘキシルメチル、ベンジル、クロロベンジル、シクロペンチル、シクロヘキシル、シクロヘプチル、アダマンチル、フェニルまたはクロロフェニルであり；
（３）Ｒ²は水素またはハロゲンであり、ＺはＣＨまたはＮであり、好ましくはＲ²は水素でＺはＮであるか、またはＲ²はハロゲンでＺはＣＨであり、より好ましくは、Ｒ²は水素でＺはＮであるか、またはＲ²はフッ素または塩素でＺはＣＨであり；
（４）Ｘは

である（式中、好ましくはＲ³は−ＯＨもしくはハロゲン置換されたアリールで置換されてもよい低級アルキル、または低級アルカノイルであり、より好ましくは、Ｒ³は低級アルキルまたは低級アルカノイルであり、より好ましくは、Ｒ³はメチルまたはアセチルであり、最も好ましくは、Ｒ³はメチルであり、およびＲ⁴は水素または低級アルキルであり、より好ましくは、Ｒ⁴は水素またはメチルであり、最も好ましくは、Ｒ⁴は水素である）。
（５）Ｙはヒドロキシ、アリール、アリール（低級）アルコキシ、または低級アルキルでモノ−またはジ−置換されてもよいカルバモイルで置換されてもよい低級アルキレンであり、好ましくはＹは低級アルキレンであり、より好ましくは、Ｙはエチレン、メチルメチレン、エチルメチレン、イソプロピルメチレン、プロピレンまたはイソブチルメチレンである。；
（６）上述の（１）〜（５）のうち２つまたはそれ以上を組み合わせた化合物である、式（Ｉ）を有する化合物。 (1) a compound of the following formula (I ′);

(2) R ¹ is hydrogen, lower alkyl, cyclo (lower) alkyl (lower) alkyl, cyclo (higher) alkyl (lower) alkyl, optionally substituted ar (lower) alkyl, heteroaryl (lower) alkyl, cyclo (Lower) alkyl, cyclo (higher) alkyl, optionally substituted aryl, lower alkylheterocyclyl, aryl-fused cyclo (lower) alkyl, preferably R ¹ is cyclo (lower) alkyl (lower) alkyl, Ar (lower) alkyl optionally substituted with halogen, cyclo (lower) alkyl, cyclo (higher) alkyl, or aryl optionally substituted with halogen, more preferably R ¹ is cyclohexylmethyl, benzyl, chlorobenzyl, Cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, phenyl Is chlorophenyl;
(3) R ² is hydrogen or halogen, Z is CH or N, preferably R ² is hydrogen and Z is N, or R ² is halogen and Z is CH, more preferably R ² is hydrogen and Z is N, or R ² is fluorine or chlorine and Z is CH;
(4) X is

Wherein R ³ is preferably lower alkyl optionally substituted with —OH or halogen-substituted aryl, or lower alkanoyl, more preferably R ³ is lower alkyl or lower alkanoyl, and more Preferably R ³ is methyl or acetyl, most preferably R ³ is methyl, and R ⁴ is hydrogen or lower alkyl, more preferably R ⁴ is hydrogen or methyl, most preferably R ⁴ is hydrogen).
(5) Y is hydroxy, aryl, aryl (lower) alkoxy, or lower alkylene optionally substituted with carbamoyl which may be mono- or di-substituted with lower alkyl, preferably Y is lower alkylene; More preferably, Y is ethylene, methylmethylene, ethylmethylene, isopropylmethylene, propylene or isobutylmethylene. ;
(6) A compound having the formula (I), which is a compound obtained by combining two or more of the above (1) to (5).

であり、
Ｒ³は−ＯＨもしくはハロゲン置換されたアリールで置換されてもよい低級アルキル、または低級アルカノイルであり、
Ｒ⁴は水素または低級アルキルであり、
Ｙはヒドロキシ、アリール、アリール（低級）アルコキシ、または低級アルキルでモノ−またはジ−置換されてもよいカルバモイルで置換されてもよい低級アルキレンである上記の（１）の化合物。 (7) R ¹ is hydrogen, lower alkyl, cyclo (lower) alkyl (lower) alkyl, cyclo (higher) alkyl (lower) alkyl, optionally substituted ar (lower) alkyl, heteroaryl (lower) alkyl, cyclo (Lower) alkyl, cyclo (higher) alkyl, optionally substituted aryl, lower alkylheterocyclyl, aryl-fused cyclo (lower) alkyl,
R ² is hydrogen or halogen;
Z is CH or N;
X is

And
R ³ is lower alkyl optionally substituted with —OH or halogen-substituted aryl, or lower alkanoyl;
R ⁴ is hydrogen or lower alkyl,
The compound of (1) above, wherein Y is hydroxy, aryl, aryl (lower) alkoxy, or lower alkylene optionally substituted with carbamoyl which may be mono- or di-substituted with lower alkyl.

であり、
Ｒ³は低級アルキルまたは低級アルカノイルであり、
Ｒ⁴は水素または低級アルキルであり、
Ｙは低級アルキレンである上記の（７）の化合物。 (8) R ¹ is cyclo (lower) alkyl (lower) alkyl, halogen-substituted al (lower) alkyl, cyclo (lower) alkyl, cyclo (higher) alkyl, or halogen-substituted aryl,
R ² is hydrogen and Z is N, or R ² is halogen and Z is CH,
X is

And
R ³ is lower alkyl or lower alkanoyl;
R ⁴ is hydrogen or lower alkyl,
The compound of (7) above, wherein Y is lower alkylene.

であり、
Ｒ³はメチルまたはアセチルであり、
Ｒ⁴は水素またはメチルであり、
Ｙはエチレン、メチルメチレン、エチルメチレン、イソプロピルメチレン、プロピレン、またはイソブチルメチレンである上記の（８）の化合物。 (9) R ¹ is cyclohexylmethyl, benzyl, chlorobenzyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, phenyl, or chlorophenyl;
R ² is hydrogen and Z is N, or R ² is fluorine or chlorine and Z is CH,
X is

And
R ³ is methyl or acetyl;
R ⁴ is hydrogen or methyl;
The compound of (8) above, wherein Y is ethylene, methylmethylene, ethylmethylene, isopropylmethylene, propylene, or isobutylmethylene.

(Test method)
In order to show the usefulness of the compound (I) of the present invention, the pharmacological test results of representative compounds of the present invention are shown below.

(Test 1: Measurement of histone deacetylase inhibitory activity)
The partial purification of human histone deacetylase, the preparation of [ ³ H] acetyl histone, and the assay for histone deacetylase activity were basically performed as follows according to the method proposed by Yoshida et al. .

(Partial purification of human histone deacetylase)
Human histone deacetylase was partially purified from human T cell leukemia Jurkat cells. Jurkat cells (5 × 10 ⁸ cells) were suspended in 40 mL of HDA buffer consisting of 15 mM potassium phosphate, pH 7.5, 5% glycerol and 0.2 mM EDTA. After homogenization, nuclei were collected by centrifugation (35,000 × g, 10 minutes) and homogenized in 20 mL of the same buffer supplemented with 1M (NH ₄ ) ₂ SO ₄ . The viscous homogenate was sonicated, clarified by centrifugation (35,000 × g, 10 min), and the deacetylase was precipitated by increasing the concentration of (NH ₄ ) ₂ SO ₄ to 3.5M. The precipitated protein was dissolved in 10 mL of HDA buffer and dialyzed against 4 liters of the same buffer. The dialysate was then loaded onto a DEAE-cellulose (Whatman DE52) column (25 x 85 mm) equilibrated with the same buffer and eluted with 300 mL of linear gradient (0-0.6 M) NaCl. A single peak of histone deacetylase activity appeared between 0.3 and 0.4 M NaCl.

(Preparation of [ ³ H] acetylhistone)
In 20 mL of RPMI-1640 medium (supplemented with 10% FBS, penicillin (50 units / mL) and streptomycin (50 μg / mL)) to obtain [ ³ H] acetyl-labeled histone as substrate for histone deacetylase assay 1 × 10 ⁸ cells of 300 MBq [ ³ H] sodium acetate in a 75 cm ³ flask in 5% CO ₂ -95% air atmosphere in the presence of 5 mM sodium butyrate for 30 minutes at 37 ° C. Incubated with, transferred to a centrifuge tube (50 mL), collected by centrifugation at 1000 rpm for 10 minutes, and washed once with phosphate buffered saline. The washed cells were suspended in 15 mL of ice-cold lysis buffer (10 mM Tris-HCl, 50 mM sodium bisulfite, 1% Triton X-100, 10 mM MgCl ₂ , 8.6% sucrose, pH 6.5). After homogenization (30 strokes) with a Dounce homogenizer, the nuclei were collected by centrifugation at 1000 rpm for 10 minutes, washed three times with 15 mL of lysis buffer, and ice-cooled washing buffer (10 mM Tris-HCl, 13 mM EDTA, pH 7. 4) Washed once with 15 mL. The pellet was suspended in 6 mL of ice-cold water using a mixer, and 68 μL of H ₂ SO ₄ was added to the suspension to a concentration of 0.4N. After incubation at 4 ° C. for 1 hour, the suspension was centrifuged at 15,000 rpm for 5 minutes, the supernatant was taken and mixed with 60 mL of acetone. After overnight incubation at −20 ° C., the coagulated material was collected by microcentrifugation, air dried and stored at −80 ° C.

(Assay for histone deacetylase activity)
As a standard assay, 10 μL of [ ³ H] acetyl labeled histone was added to 90 μL of the enzyme fraction and the mixture was incubated at 25 ° C. for 30 minutes. The reaction was stopped by adding 10 μL of aqueous HCl. The released [ ³ H] acetic acid was extracted with ethyl acetate (1 mL), the solvent layer (0.9 mL) was taken up in 10 mL of toluene scintillation solution, and the radioactivity was measured.

(Test 2: Determination of T cell proliferation inhibitory activity)
Lewis rat spleen cells in 0.1 mL RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS), 50 mM 2-mercaptoethanol, penicillin (100 units / mL) and streptomycin (100 μg / mL) A T lymphocyte blastogenesis test was performed in a microtiter plate containing 5 × 10 ⁵ cells in each well, and concanavalin A (1 μg / mL) was added thereto. Cells were incubated for 72 hours at 37 ° C. in a humidified 5% CO ₂ atmosphere. After the culture period, the inhibitory activity of the test compound in the T lymphocyte blastogenesis reaction was quantified by the AlamarBlue (registered trademark) assay. The sample was dissolved in DMSO, further diluted with RPMI-1640 medium, and added to the medium. The activity of the test compound was expressed as IC ₅₀ .

The results of those tests are shown in Table 1.
Table 1: HDAC inhibitory activity and T cell proliferation inhibitory activity of compounds of the present invention

  The Ames test is negative and the target compound is not predicted to reduce blood platelets / neutrophils, decrease blood pressure, or increase heart rate at its effective dose. .

The pharmaceutical composition of the present invention comprising a histone deacetylase inhibitor such as compound (I) is used for inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukemia ( APL), protozoan infections and the like are useful as therapeutic or prophylactic agents for diseases caused by abnormal gene expression. Furthermore, it is useful as an antitumor agent or an immunosuppressive agent for preventing organ transplant rejection and autoimmune diseases exemplified below:
Rejection by transplantation of organs or tissues such as heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, intervertebral disc, trachea, myoblast, cartilage, etc .;
Graft-versus-host reaction after bone marrow transplantation;
Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, etc .; Infections.

  Furthermore, pharmaceutical preparations of histone deacetylase inhibitors such as compound (I) are useful for the treatment or prevention of the following diseases.

Inflammatory or hyperproliferative skin diseases or immune-mediated skin diseases (eg psoriasis, atopic dermatitis, contact dermatitis, eczema-like dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous Pemphigus, epidermolysis bullosa, hives, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, etc.);
Autoimmune diseases of the eye (eg, keratoconjunctivitis, spring catarrh, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, corneal vitiligo, pemphigoid, Mohren ulcer, sclera Inflammation, Graves eye disorder, Fogt-Koyanagi-Harada syndrome, dry keratoconjunctivitis (dry eye), frickten, iridocyclitis, sarcoidosis, endocrine eye disorder, etc.);
Reversible obstructive airway disease [asthma (eg bronchial asthma, allergic asthma, endogenous asthma, extrinsic asthma, dust asthma, etc.), especially chronic or refractory asthma (eg late asthma, increased airway responsiveness, etc.) , Bronchitis, etc.];
Mucosal or vascular inflammation (eg gastric ulcer, ischemic or thrombotic vascular injury, ischemic bowel disease, enteritis, necrotizing enterocolitis, burn-related bowel damage, leukotriene B4 mediated disease, etc.);
Intestinal inflammation / allergy (eg celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, etc.);
Food-related allergic diseases with symptomatic manifestations of distant gastrointestinal tract (eg migraine, rhinitis, eczema)
Kidney disease (eg, interstitial nephritis, Goodpasture syndrome, hemolytic uremic syndrome, diabetic nephropathy, etc.);
Neurological diseases (eg, polymyositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, solitary neuritis, cerebral infarction, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), radiculopathy, etc. );
Cerebral ischemic disease (eg head injury, cerebral hemorrhage (eg subarachnoid hemorrhage, intracerebral hemorrhage, etc.), cerebral thrombosis, cerebral embolism, cardiac arrest, stroke, transient ischemic attack (TIA), hypertensive Brain disorders);
Endocrine disorders (eg, hyperthyroidism, Graves'disease);
Hematological disorders (eg erythroblastic fistula, aplastic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, granulocytopenia, pernicious anemia, giant erythroblastic anemia, erythropoiesis Failure);
Bone disease (eg osteoporosis);
Respiratory diseases (eg sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia);
Skin diseases (eg dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photosensitivity, cutaneous T-cell lymphoma);
Cardiovascular disease (eg, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, etc.);
Collagen disease (eg scleroderma, Wegener's granulomas, Sjogren's syndrome, etc.)
Adiposity;
Eosinophilic fasciitis;
Periodontal disease (eg damage to gingiva, periodontal, alveolar bone or cementum);
Nephrotic syndrome (eg glomerulonephritis);
Androgenetic alopecia, senile alopecia;
Muscular dystrophy;
Pyoderma and Sezary syndrome;
Chromosome abnormality-related diseases (eg Down syndrome)
Addison's disease;
Active oxygen-mediated diseases {eg, ischemic circulatory disorders in organs (eg, heart, liver, kidney, gastrointestinal tract, etc.) associated with organ damage [eg, preservation, transplantation, ischemic disease (eg, embolism, myocardial infarction, etc.), etc.] ];
Bowel disease (eg endotoxin shock, pseudomembranous colitis, drug or radiation induced colitis);
Kidney disease (eg, ischemic acute renal dysfunction, chronic renal failure);
Lung disease (eg, poisoning caused by lung oxygen or drugs (eg, paraquat, bleomycin, etc.), lung cancer, emphysema, etc.);
Eye diseases (eg, cataracts, iron deposition diseases (iron rust), retinitis, pigment degeneration, senile spots, vitreous scars, alkaline burns of the cornea, etc.);
Dermatitis (eg polymorphic erythema, linear immunoglobulin A dermatitis, cement dermatitis, etc.); and other diseases (eg gingivitis, periodontitis, sepsis, pancreatitis, environmental pollution (eg air pollution, etc.) ), Diseases caused by aging, carcinogens, cancer metastasis, altitude sickness, etc.)};
Diseases caused by histamine release or leukotriene C4 release;
Restenosis of coronary arteries after angioplasty and prevention of adhesion after surgery;
Autoimmune diseases and inflammatory symptoms (eg primary mucosal edema, autoimmune atrophic gastritis, premature menopause, male infertility, juvenile diabetes, pemphigus vulgaris, pemphigus vulgaris, sympathetic ophthalmitis, lens source) Uveitis, idiopathic leukopenia, active chronic hepatitis, idiopathic cirrhosis, discoid lupus erythematosus, autoimmune orchitis, arthritis (eg osteoarthritis, etc.);
Human immunodeficiency virus (HIV) infection, AIDS;
Allergic conjunctivitis;
Hypertrophic scar, keloid, intimal hyperplasia due to trauma, burns or surgery.

  In addition, HDAC inhibitors have the potential to prevent restenosis in patients undergoing treatment of coronary artery disease, particularly percutaneous transluminal coronary angioplasty (PTCA), as anti-proliferative agents.

  Therefore, the pharmaceutical composition of the present invention can be used for liver diseases [eg, immunogenic diseases (eg, chronic autoimmune liver diseases such as autoimmune liver disease, primary biliary cirrhosis, sclerosing cholangitis), partial Liver resection, acute liver necrosis (eg, necrosis caused by toxins, viral hepatitis, shock, hypoxia, etc.), hepatitis B, non-A non-B hepatitis, cirrhosis, liver failure (eg, fulminant hepatitis, late onset) Hepatic hepatitis, “chronic to acute” liver failure (such as acute liver failure in chronic liver disease), etc.), etc.].

  The pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, a solid, semi-solid or liquid form, which contains a histone deacetylase inhibitor such as compound (I) as an active ingredient. Contains in admixture with organic or inorganic carriers or excipients suitable for topical, enteric or parenteral administration. The active ingredients are, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, injections, ointments, coatings, eye drops, lotions, gels, creams and other suitable for use. It may be formulated with conventional non-toxic pharmaceutically acceptable carriers for dosage forms.

  Carriers that can be used in the present invention are water, glucose, lactose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, and solid, semi-solid Other carriers suitable for use in the manufacture of formulations in solid or liquid form are included. In addition, adjuvants, stabilizers, thickeners, solubilizers, colorants and fragrances can be used.

  For this composition to be applied to humans, it is preferably applied by intravenous, intramuscular, topical or oral administration or by a vascular stent impregnated with compound (I). The therapeutically effective amount of a histone deacetylase inhibitor, such as compound (I), will vary depending on and depends on the age and symptoms of the individual patient being treated, but can be administered intravenously when treating an individual patient. In the case of a daily dose of 0.01 to 10 mg / kg of human body weight of a histone deacetylase inhibitor such as compound (I), or in the case of intramuscular administration, a histone deacetylase such as a compound of formula (I) Daily doses of 0.1-10 mg / kg human body weight of acetylase inhibitor and, if administered orally, daily doses of histone deacetylase inhibitor such as compound (I) / kg human body weight 0.5-50 mg is generally administered therapeutically.

  In producing the above pharmaceutical dosage form, Compound (I) or a salt thereof can be used together with other immunosuppressive substances such as rapamycin, mycophenolic acid, cyclosporin A, tacrolimus or brequinar sodium.

  Below, the reaction in a manufacture example and an Example for preparing compound (I) of this invention is demonstrated in detail. The present invention should in no way be limited by the following production examples and examples.

The following abbreviations are also used herein: HCl (hydrogen chloride); MeOH (methanol); EtOH (ethanol); IPE (diisopropyl ether); AcOH (acetic acid); AcOEt (ethyl acetate); HOBT (1- Hydroxybenzotriazole); WSCD (1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide); DMF (N, N-dimethylformamide); DMA (N, N-dimethylacetamide); aq. (Aqueous solution); Et ₃ N (triethylamine); DIEA (diisopropylethylamine); NaOH (sodium hydroxide); NaH (sodium hydride); THF (tetrahydrofuran); DIBAL (diisobutylaluminum hydride); LAH (lithium aluminum hydride) LiBH ₄ (lithium borohydride); NaBH ₄ (sodium borohydride); MnO ₂ (manganese (IV) oxide).

(Production Example 1)
To a solution of ethyl 5-chloro-6-[(2-phenoxyethyl) amino] nicotinate (1.6 g) in THF (24.0 mL) was added 0.94 M DIBAL hexane solution (15.9 mL) under a nitrogen atmosphere. One drop at a time was added and the mixture was stirred at the same temperature for 1 hour. After adding MeOH (3.0 mL) and potassium sodium tartrate tetrahydrate (4.2 g) at 0 ° C., the mixture was stirred at ambient temperature for 1 hour. The isolated precipitate was filtered and the solvent removed by concentration to give {5-chloro-6-[(2-phenoxyethyl) amino] -3-pyridinyl} methanol (1.26 g).

  The compounds disclosed in Production Examples 2, 3, 4, 5, 6, 7, 8, 9 and 10 were obtained in the same manner as in Production Example 1.

(Production Example 11)
A solution of (2R) -2-amino-N-benzyl-N-methylpropanamide (1.7 g) in THF (5.1 mL) was added to a mixture of LAH (1.68 g) in THF (34.0 mL) under a nitrogen atmosphere. At 50 ° C., and the mixture was stirred for 2 hours with heating under reflux. After adding water (1.68 mL), 4N-NaOHaq. (1.68 mL) and water (5.04 mL). The isolated precipitate was filtered and the solvent removed by concentration to give (2R) -N ¹ -benzyl-N ¹ -methyl-1,2-propanediamine (1.43 g).

  The compounds disclosed in Production Examples 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22 were obtained in the same manner as in Production Example 11.

(Production Example 23)
To a solution of ethyl 5-chloro-6-({2-[(4-fluorobenzyl) (methyl) amino] -2-oxoethyl} amino) nicotinate (3.5 g) in THF (70 mL) was added LiBH ₄ (1. 2 g) was added under ice cooling and the mixture was stirred at ambient temperature for 40 hours. 1N HCl aq. (60.0 mL) was added under ice cooling, and then the mixture was adjusted to pH 9 with potassium carbonate. The mixture was extracted with AcOEt and the extracted layer was evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of chloroform and MeOH (19: 1 v / v) as eluent. Fractions containing the desired product are collected and evaporated in vacuo to give 2-{[3-chloro-5- (hydroxymethyl) -2-pyridinyl] amino} -N- (4-fluorobenzyl) -N-methylacetamide (0.71 g) was obtained.

  The compounds disclosed in Production Examples 24, 25, 26, 27 and 28 were obtained in the same manner as in Production Example 23.

(Production Example 29)
To a mixture of ethyl 5-chloro-6-({2-[(4-fluorobenzoyl) amino] -2-methylpropyl} amino) nicotinate (1.25 g) in THF (25 mL) was added LiBH4 (0. 84 g) was added and the mixture was stirred at ambient temperature for 20 hours. To the reaction mixture was added 1N HCl aq. (44.4 mL) was added dropwise under ice cooling. After pouring the mixture into a mixture of AcOEt and ice water, the mixture was adjusted to pH 9.0 with 20% aqueous potassium carbonate. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give N- [2-{[3-chloro-5- (hydroxymethyl) -2-pyridinyl] amino} -1,1- Dimethylethyl) -4-fluorobenzamide (1.08 g) was obtained.

(Production Example 30)
A mixture of {5-chloro-6-[(2-phenoxyethyl) amino] -3-pyridinyl} methanol (1.2 g) and MnO ₂ (3.7 g) in chloroform (24.0 mL) Stir for hours. Magnesium oxide was filtered and the solvent removed by concentration. The residue was triturated with IPE and hexane to give 5-chloro-6-[(2-phenoxyethyl) amino] nicotinaldehyde (0.78 g).

  The compounds disclosed in Production Examples 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 and 46 were obtained in the same manner as in Production Example 30. It was.

(Production Example 47)
A mixture of (6-{[2- (4-fluorophenoxy) ethyl] amino} -3-pyridinyl) methanol (0.55 g) and MnO ₂ (1.8 g) in chloroform (11.0 mL) at 60 ° C. Stir for 2 hours. Manganese oxide was filtered off and the solvent removed by concentration to give 6-{[2- (4-fluorophenoxy) ethyl] amino} nicotinaldehyde (0.53 g).

  The compounds disclosed in Production Examples 48 and 49 were obtained in the same manner as in Production Example 47.

(Production Example 50)
A mixture of ethyl 5-chloro-6-[(2-methoxyethyl) amino] nicotinate (2.0 g) and NaBH ₄ (1.2 g) in THF (20 mL) was refluxed with MeOH (6.3 mL). One drop was added and stirred at the same temperature for 4 hours. The solvent was removed by concentration. Water was added to the residue and extracted with AcOEt. The extract layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give {5-chloro-6-[(2-methoxyethyl) amino] -3-pyridinyl} methanol (1.46 g).

  The compound disclosed in Production Example 51 was obtained in the same manner as in Production Example 50.

(Production Example 52)
To a mixture of ethyl 6-({2-[(tert-butoxycarbonyl) amino] ethyl} amino) -5-chloronicotinate (5.4 g) and NaBH ₄ (2.4 g) in THF (54.0 mL). MeOH (6.4 mL) was added dropwise at 50-56 ° C. and the mixture was stirred for 2.5 hours with heating under reflux. The solvent was removed by concentration, and AcOEt and water were added to the residue. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of chloroform and AcOEt as eluent. The elution fraction containing the desired product was collected and evaporated in vacuo (2-{[3-chloro-5- (hydroxymethyl) -2-pyridinyl] amino} ethyl) tert-butyl carbamate. (3.51 g) was obtained.

(Production Example 53)
(2E) -3- {5-[(2-phenoxyethyl) amino] -2-pyrazinyl} acrylic acid (0.5 g) in DMF (10.0 mL), O- (tetrahydro-2H-pyran-2- Yl) To a mixture of hydroxylamine (0.25 g) and HOBT (0.28 g) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.33 g) and the mixture was stirred at ambient temperature for 20 hours. . The reaction mixture was poured into a mixture of IPE (50 mL) and water (30 mL) and stirred for 30 minutes. The isolated precipitate was collected by filtration to give (2E) -3- {5-[(2-phenoxyethyl) amino] -2-pyrazinyl} -N- (tetrahydro-2H-pyran-2-yloxy) acrylamide (0. 62 g) was obtained.

(Production Example 54)
(2E) -3- {5-Chloro-6-[(2-phenoxyethyl) amino] -3-pyridinyl} acrylic acid (0.6 g) in DMF (9.0 mL), O- (tetrahydro-2H- To a mixture of pyran-2-yl) hydroxylamine (0.27 g) and HOBT (0.31 g) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.35 g) and the mixture was at ambient temperature. Stir for 20 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give (2E) -3- {5-chloro-6-[(2-phenoxyethyl) amino] -3-pyridinyl} -N. -(Tetrahydro-2H-pyran-2-yloxy) acrylamide (0.76 g) was obtained.

  The compounds disclosed in Preparation Examples 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 and 75 are the same as in Preparation Example 54. Obtained by the method.

(Production Example 72)
(2E) -3- [5-Chloro-6-({2-[(4-chlorobenzoyl) amino] ethyl} amino) -3-pyridinyl] acrylic acid (0.5 g) in DMF (10.0 mL) To a mixture of O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.19 g) and HOBT (0.21 g) was added WSCD (0.25 g) and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into a mixture of AcOEt, THF and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with ether to give 4-chloro-N- {2-[(3-chloro-5-{(1E) -3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy) amino]- 1-propen-1-yl} -2-pyridinyl) amino] ethyl} benzamide (0.55 g) was obtained.

  The compounds disclosed in Production Examples 73 and 74 were obtained in the same manner as in Production Example 72.

(Production Example 76)
To a mixture of 5,6-dichloronicotinic acid (5.0 g) and N-methoxymethanamine hydrochloride (3.1 g) in dichloromethane (50 mL) was added WSCD (4.9 g) and the mixture was stirred at ambient temperature for 2 hours. did. The reaction mixture was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE and hexanes to give 5,6-dichloro-N-methoxy-N-methylnicotinic acid amide (4.77 g).

(Production Example 77)
To a mixture of ethyl diethoxyphosphoryl acetate (2.67 mL) and 60% NaH (0.54 g) stirring in THF (27 mL), {2-[(3-chloro-5-formyl-2-pyridinyl) amino] A solution of tert-butyl ethyl} carbamate (3.1 g) in THF (10 mL) was added dropwise under ice cooling and the mixture was then stirred at ambient temperature for 2.5 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give (2E) -3- [6-({2-[(tert-butoxycarbonyl) amino] ethyl} amino) -5- Chloro-3-pyridinyl] ethyl acrylate (3.8 g) was obtained.

(Production Example 78)
A mixture of 5-chloro-6-[(2-phenoxyethyl) amino] nicotinaldehyde (0.70 g), malonic acid (0.53 g) and piperidine (54 mg) in pyridine (6.1 mL) at 4 Stir for hours. The solvent was removed by concentration and a mixture of AcOEt, THF and water was added to the residue. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE and hexane to give (2E) -3- {5-chloro-6-[(2-phenoxyethyl) amino] -3-pyridinyl} acrylic acid (0.79 g).

  The compounds disclosed in Production Examples 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93 and 94 were obtained in the same manner as in Production Example 78. It was.

(Production Example 95)
A mixture of 6-{[2- (4-fluorophenoxy) ethyl] amino} nicotinaldehyde (0.5 g), malonic acid (0.4 g) and piperidine (41 mg) in pyridine (4.7 mL) at 100 ° C. Stir for 3 hours. The solvent was removed by concentration, and a mixture of AcOEt (5 mL), IPE (15 mL) and water (15 mL) was added to the residue with stirring. The isolated precipitate was collected by filtration to give (2E) -3- (6-{[2- (4-fluorophenoxy) ethyl] amino} -3-pyridinyl) acrylic acid (0.42 g).

(Production Example 96)
N- {2-[(3-Chloro-5-formyl-2-pyridinyl) amino] -1,1-dimethylethyl} -4-fluorobenzamide (0.90 g), malonic acid in pyridine (6.2 mL) (0.54 g) and piperidine (55 mg) were stirred at 100 ° C. for 3 hours. The solvent was removed by concentration, and AcOEt and water were added to the residue. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE to give (2E) -3- [5-chloro-6-({2-[(4-fluorobenzoyl) amino] -2-methylpropyl} amino) -3-pyridinyl] acrylic acid (0 .72 g) was obtained.

(Production Example 97)
(2E) -3- (5-Chloro-2-pyrazinyl) methyl acrylate (1.0 g), (2R) -2-amino-N- (cyclohexylmethyl) butanamide (1.5 g) and Et ₃ N (2 .11 mL) in DMA (10 mL) was stirred at 115 ° C. for 10 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE to give methyl (2E) -3- [5-({(1R) -1-[(cyclohexylmethyl) carbamoyl] propyl} amino) pyrazin-2-yl] acrylate (1.23 g). Obtained.

  Production Examples 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259 and 260 are the same as those of Preparation Example 97. Obtained by the method.

(Production Example 125)
1,3-Dimethyl-2-imidazolidinone (30 g) of ethyl 5,6-dichloronicotinate (3.0 g), 2-methyl-1,2-propanediamine (1.7 g) and DIEA (5.2 mL) The solution was stirred at 100 ° C. for 3.5 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl 6-[(2-amino-2-methylpropyl) amino] -5-chloronicotinate (3.15 g). It was.

(Production Example 126)
Methyl (2E) -3- (5-chloro-2-pyrazinyl) acrylate (0.5 g), (2R) -N ¹ -benzyl-N ¹ -methyl-1,2-propanediamine (0.67 g) and A solution of Et ₃ N (1.05 mL) in DMA (5.0 mL) was stirred at 100 ° C. for 7 hours. The reaction mixture was saturated sodium bicarbonate aq. And extracted with a mixture of AcOEt and THF. The extract layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of chloroform and MeOH (19: 1 v / v) as eluent. Elution fractions containing the desired product were collected and evaporated in vacuo to give (2E) -3- [5-({(1R) -2- [benzyl (methyl) amino] -1-methylethyl. } Amino) -2-pyrazinyl] methyl acrylate (0.71 g) was obtained.

  The compounds disclosed in Production Examples 127, 128, 129, 130, 131, 132, 133, 134, 135, 136 and 137 were obtained in the same manner as in Production Example 126.

(Production Example 138)
(2E) -3- (5-Chloro-2-pyrazinyl) acrylic acid methyl ester (0.5 g), [2- (2-chlorophenoxy) ethyl] amine (0.65 g) and Et ₃ N (1.05 mL) Of DMA (5.0 mL) was stirred at 100 ° C. for 5 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give (2E) -3- (5-{[2- (2-chlorophenoxy) ethyl] amino} -2-pyrazinyl) acrylic. Methyl acid (0.72 g) was obtained.

  The compounds disclosed in Production Examples 139, 140, 141, 142, 143, 144, 145, 146 and 147 were obtained in the same manner as in Production Example 138.

(Production Example 148)
Methyl (2E) -3- (6-chloro-2-pyrazinyl) acrylate (0.6 g), (2-phenoxyethyl) amine (0.48 mL), cesium carbonate (1. 2 mL) in dioxane (12.0 mL). 48 g), 1,1′-binaphthalene-2,2′-diylbis (diphenylphosphine) (0.19 g) and palladium (II) acetate (34.0 mg) were heated under reflux for 2 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of hexane and AcOEt (7: 3 v / v) as eluent. Elution fractions containing the desired product were collected and evaporated in vacuo to give methyl (2E) -3- {6-[(2-phenoxyethyl) amino] -2-pyrazinyl} acrylate (0. 75 g) was obtained.

(Production Example 149)
Methyl (2E) -3- (5-chloro-2-pyrazinyl) acrylate (1.1 g), tert-butyl [(2R) -2-aminopropyl] carbamate (1.45 g) and Et ₃ N (2 .32 mL) in DMA (11 mL) was stirred at 100 ° C. for 12 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE and methyl (2E) -3- [5-({(1R) -2-[(tert-butoxycarbonyl) amino] -1-methylethyl} amino) pyrazin-2-yl] acrylate (1.0 g) was obtained.

  The compounds disclosed in Production Examples 150 and 151 were obtained in the same manner as in Production Example 149.

(Production Example 152)
A solution of ethyl 5,6-dichloronicotinate (1.2 g), 2-phenoxyethanamine (0.79 mL) and potassium carbonate (2.26 mL) in DMF (12.0 mL) was stirred at 100 ° C. for 4 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl 5-chloro-6-[(2-phenoxyethyl) amino] nicotinate (1.67 g).

  The compounds disclosed in Production Examples 153, 154, 155, 156, 157, 158, 159, 160, 161 and 162 were obtained in the same manner as in Production Example 152.

(Production Example 163)
Ethyl 5,6-dichloronicotinate (5.0 g) in 1,3-dimethyl-2-imidazolidinone (50.0 mL), N- (4-fluorobenzyl) -N-methylglycinamide hydrochloride (6 .3 g) and DIEA (8.7 mL) were stirred at 100 ° C. for 4.5 hours. The reaction mixture was poured into a mixture of water and extracted with AcOEt. The extract layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE to give ethyl 5-chloro-6-({2-[(4-fluorobenzyl) (methyl) amino] -2-oxoethyl} amino) nicotinate (7.57 g).

  The compounds disclosed in Production Examples 164, 165, 166, 167 and 168 were obtained in the same manner as in Production Example 163.

(Production Example 169)
(2E) -3- (5,6-Dichloropyridin-3-yl) methyl acrylate (0.5 g), Et ₃ N (0.9 mL) and (2R) -2-amino-N- (cyclohexylmethyl) A solution of propanamide (0.6 g) in DMA (5.0 mL) was stirred at 145 ° C. for 12 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of dichloromethane and AcOEt (4: 1 v / v) as eluent. The elution fraction containing the desired product was collected and evaporated in vacuo to (2E) -3- [5-chloro-6-({(1R) -2-[(cyclohexylmethyl) amino]- 1-methyl-2-oxoethyl} amino) pyridin-3-yl] methyl acrylate (0.32 g) was obtained.

  The compound disclosed in Production Example 170 was obtained in the same manner as in Production Example 169.

(Production Example 171)
A solution of ethyl 5,6-dichloronicotinate (5.0 g), tert-butyl (2-aminoethyl) carbamate (4.0 g) and potassium carbonate (9.4 g) in DMF (50.0 mL) at 100 ° C. Stir for 3.5 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE to give ethyl 6-({2-[(tert-butoxycarbonyl) amino] ethyl} amino) -5-chloronicotinate (5.55 g).

(Production Example 172)
Methyl (2E) -3- {5-[(2-phenoxyethyl) amino] -2-pyrazinyl} acrylate (0.55 g) and 1N in a solution of MeOH (11.0 mL) and THF (8.0 mL) -NaOH aq. A mixture of (5.5 mL) was stirred at ambient temperature for 18 hours. The solvent was removed by concentration. AcOEt and brine were added to the residue and 1N HCl aq. The mixture was adjusted to pH 5 with. The separated organic layer was dried over magnesium sulfate and evaporated in vacuo to give (2E) -3- {5-[(2-phenoxyethyl) amino] -2-pyrazinyl} acrylic acid (0.51 g). .

(Production Example 173)
Ethyl (2E) -3- [5-chloro-6-({2-[(4-chlorobenzoyl) amino] ethyl} amino) -3-pyridinyl] acrylate (0.6 g) in MeOH (12 mL) and 1N-NaOH aq. (7.3 mL) was stirred at 60 ° C. for 2 hours. The solvent was removed by concentration. To the residue was added a mixture of AcOEt and water and the mixture was adjusted to pH 5 with 1N HCl. The separated organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE to give (2E) -3- [5-chloro-6-({2-[(4-chlorobenzoyl) amino] ethyl} amino) -3-pyridinyl] acrylic acid (0.52 g). Obtained.

  The compounds disclosed in Production Examples 174 and 175 were obtained in the same manner as in Production Example 173.

(Production Example 176)
Methyl (2E) -3- [5-({(1R) -1-[(cyclohexylmethyl) carbamoyl] propyl} amino) pyrazin-2-yl] acrylate (1.2 g) and 1N in MeOH (24 mL) -NaOH aq. A mixture of (8.3 mL) was stirred at 60 ° C. for 2.5 hours. For the reaction mixture, 1 N HCl aq. Neutralize with (8.3 mL) and evaporate the mixture in vacuo. To the residue in DMF (12 mL) was added O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.59 g), HOBT (0.68 g) and WSCD (0.78 g) and the mixture at ambient temperature. Stir for 20 hours. The reaction mixture was treated with IPE and 2% sodium bicarbonate aq. The mixture was poured into the mixture with stirring. The isolated precipitate was collected by filtration to give (2R) -N- (cyclohexylmethyl) -2-[(5-{(1E) -3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy) amino] Proprop-1-en-1-yl} pyrazin-2-yl) amino] butanamide (0.82 g) was obtained.

  Production Examples 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 261, 262, The compounds disclosed in 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275 and 276 were obtained in the same manner as in Production Example 176.

(Production Example 199)
Methyl (2E) -3- [5-({(1R) -1- [benzylcarbamoyl] -4-methylpentyl} amino) pyrazin-2-yl] acrylate (1.1 g) in MeOH (60 mL) and 1N-NaOH aq. (29 mL) was stirred at 60 ° C. for 3 hours. The reaction mixture was diluted with 1N HCl aq. Neutralized with (29 mL) and evaporated under reduced pressure. The residue was extracted twice with chloroform. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. To the residue in DMF (20 mL) was added O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (404 mg), HOBT (388 mg) and WSCD (670 mg) and the mixture was stirred at ambient temperature for 12 hours. A mixture of ethyl acetate and water was poured into the reaction mixture. The aqueous layer was separated and extracted twice with AcOEt. The combined organic layers were washed twice with water, dried over magnesium sulfate, filtered and evaporated. The residue was column chromatographed using a Yamazen packed column (35 × 100 mm, chloroform / AcOEt), (2R) -N-benzyl-2-[(5-{(1E) -3-oxo-3-[(tetrahydro- 2H-pyran-2-yloxy) amino] prop-1-en-1-yl} pyrazin-2-yl) amino] -4-methylpentanamide (883 mg) was obtained as amorphous.

  The compounds disclosed in Production Examples 200, 201, 202 and 203 were obtained in the same manner as in Production Example 199.

(Production Example 204)
Methyl (2E) -3- [5-({(1R) -2- [benzyl (methyl) amino] -1-methylethyl} amino) -2-pyrazinyl] acrylate (0.6 g) in MeOH (12 mL) ) And 1N-NaOH aq. (3.5 mL) of the mixture was stirred at 55 ° C. for 2.5 hours. For the reaction mixture, 1 N HCl aq. (3.5 mL) and the mixture was evaporated in vacuo. To the residue in DMF (10 mL) was added O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.31 g), HOBT (0.36 g) and WSCD (0.41 g) and the mixture at ambient temperature. Stir for 20 hours. The reaction mixture was poured into water and extracted with a mixture of AcOEt and THF. The extract layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of chloroform and MeOH (19: 1 v / v) as eluent. Elution fractions containing the desired product were collected and evaporated in vacuo to give (2E) -3- [5-({(1R) -2- [benzyl (methyl) amino] -1-methylethyl. } Amino) -2-pyrazinyl] -N- (tetrahydro-2H-pyran-2-yloxy) acrylamide (0.71 g) was obtained.

  The compounds disclosed in Production Examples 205, 206, 207, 208, 209, 210, 211, 212, 213, 214 and 215 were obtained in the same manner as in Production Example 204.

(Production Example 216)
Methyl (2E) -3- (5-{[2- (2-chlorophenoxy) ethyl] amino} -2-pyrazinyl) acrylate in a solution of MeOH (7.0 mL) and THF (7.0 mL) (0 .7g) and 1N-NaOH aq. A mixture of (4.2 mL) was stirred at 50 ° C. for 1 hour. For the reaction mixture, 1 N HCl aq. Neutralized with (4.2 mL) and the mixture was evaporated in vacuo.
To the residue in DMF (10.5 mL) was added O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.37 g), HOBT (0.43 g) and WSCD (0.49 g) and the mixture was Stir at temperature for 20 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE to give (2E) -3- (5-{[2- (2-chlorophenoxy) ethyl] amino} -2-pyrazinyl) -N- (tetrahydro-2H-pyran-2-yloxy) acrylamide (0.7 g) was obtained.

  The compounds disclosed in Production Examples 217, 218, 219, 220, 221, 222, 223, 224 and 225 were obtained in the same manner as in Production Example 216.

(Production Example 226)
(2E) -3- [5-({(1R) -2-[(4-chlorobenzoyl) amino] -1-methylethyl} amino) pyrazin-2-yl] acrylic acid in MeOH (9.4 mL) Methyl (0.47 g) and 1N-NaOH aq. A mixture of (3.8 mL) was stirred at 60 ° C. for 2.5 hours. For the reaction mixture, 1 N HCl aq. Neutralized with (3.8 mL) and the mixture was evaporated in vacuo. To the residue in DMF (10 mL) was added O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.22 g), HOBT (0.25 g) and WSCD (0.29 g) and the mixture at ambient temperature. Stir for 20 hours. The reaction mixture was poured into 2% aqueous sodium bicarbonate and extracted with a solution of AcOEt and THF. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of AcOEt and THF (9: 1 v / v) as eluent. Elution fractions containing the desired product were collected and evaporated in vacuo to give 4-chloro-N-{(2R) -2-[(5-{(1E) -3-oxo-3- [ (Tetrahydro-2H-pyran-2-yloxy) amino] prop-1-en-1-yl} pyrazin-2-yl) amino] propyl} benzamide (0.45 g) was obtained.

  The compounds disclosed in Production Examples 227, 228, 229 and 230 were obtained in the same manner as in Production Example 226.

(Production Example 231)
(2E) -3- [5-Chloro-6-({(1R) -2-[(cyclohexylmethyl) amino] -1-methyl-2-oxoethyl} amino) pyridine-3 in MeOH (9.0 mL) -Yl] methyl acrylate (0.45 g) and 4N-NaOH aq. (0.89 mL) was stirred at 55 ° C. for 3.5 hours. For the reaction mixture, 1 N HCl aq. Neutralize with (3.55 mL) and evaporate the mixture in vacuo. To the residue in DMF (9.0 mL) was added O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.21 g), HOBT (0.24 g) and WSCD (0.28 g) and the mixture was Stir at temperature for 20 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of AcOEt and hexane (3: 1 v / v) as eluent. The elution fractions containing the desired product were collected and evaporated in vacuo to give N ^2- (3-chloro-5-{(1E) -3-oxo-3-[(tetrahydro-2H-pyran- 2-yloxy) amino] prop-1-en-1-yl} pyridin-2-yl) -N ^1- (cyclohexylmethyl) -D-alaninamide (0.33 g) was obtained.

  The compound disclosed in Production Example 232 was obtained in the same manner as in Production Example 231.

(Production Example 233)
1) To a solution of 5,6-dichloro-N-methoxy-N-methylnicotinamide (4.7 g) in toluene (141.0 mL) was added a 0.99 M diisobutylaluminum hydride toluene solution (22.2 mL) under a nitrogen atmosphere. One drop was added at −30 ° C. and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was quenched with MeOH (4.1 mL) and stirred at 0 ° C. for 30 minutes. (Solution A)
2) To a solution of methyl (dimethoxyphosphoryl) acetate (3.4 mL) in toluene (103 mL), 60% NaH (0.96 g) was added in portions at 20 to 30 ° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 minutes. did. Solution A was added dropwise to the mixture at 0-10 ° C. and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured into a mixture of AcOEt and water, 1N-HCl aq. To pH 2. The separated organic layer was washed with saturated sodium bicarbonate aq. Washed with, dried over magnesium sulphate and evaporated in vacuo. The residue was triturated with IPE to give methyl (2E) -3- (5,6-dichloropyridin-3-yl) acrylate (2.83 g).

(Production Example 234)
(2E) -3- (5-{[(1R) -2-Amino-1-methylethyl] amino} pyrazin-2-yl) acrylic acid methyl dihydrochloride (0.52 g) in DMF (5.0 mL) ), Et ₃ N (0.47 mL), 4-chlorobenzoic acid (0.32 g), and HOBT (0.27 g) were mixed with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.31 g). ) And the mixture was stirred at ambient temperature for 18 hours. The reaction mixture is poured into water and IPE, and the isolated precipitate is filtered off to give (2E) -3- [5-({(1R) -2-[(4-chlorobenzoyl) amino] -1-methylethyl. } Amino) pyrazin-2-yl] methyl acrylate (0.48 g) was obtained.

  The compounds disclosed in Production Examples 235 and 236 were obtained in the same manner as in Production Example 234.

(Production Example 237)
Methyl (2E) -3- (5-{[2- (benzylamino) ethyl] amino} -2-pyrazinyl) acrylate (0.50 g), AcOH (96 mg), and HOBT in dichloromethane (10.0 mL) To the (0.24 g) mixture was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.27 g) and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into water and extracted with dichloromethane. The extract layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with ether to give methyl (2E) -3- [5-({2- [acetyl (benzyl) amino] ethyl} amino) -2-pyrazinyl] acrylate (0.47 g).

(Production Example 238)
(2E) -3- {6-[(2-Aminoethyl) amino] -5-chloro-3-pyridinyl} acrylic acid ethyl dihydrochloride (1.0 g), 4-chloro in DMF (20.0 mL) To a mixture of benzoic acid (0.5 g), Et ₃ N (0.85 mL) and HOBT (0.43 g) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.50 g) and the mixture was Stir at ambient temperature for 20 hours. The reaction mixture was saturated sodium bicarbonate aq. And poured into a mixture of AcOEt. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE and hexane to give ethyl (2E) -3- [5-chloro-6-({2-[(4-chlorobenzoyl) amino] ethyl} amino) -3-pyridinyl] acrylate (1. 18 g) was obtained.

  The compounds disclosed in Production Examples 239 and 240 were obtained in the same manner as in Production Example 238.

(Production Example 241)
4-Fluorobenzoyl chloride in a mixture of ethyl 6-[(2-amino-2-methylpropyl) amino] -5-chloronicotinate (1.0 g) and Et ₃ N (0.62 mL) in dichloromethane (10 mL) (0.44 mL) was added dropwise under ice cooling and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was saturated sodium bicarbonate aq. And poured into a mixture of chloroform. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of hexane and AcOEt (1: 1 v / v) as eluent. Elution fractions containing the desired product are collected and evaporated in vacuo to give 5-chloro-6-({2-[(4-fluorobenzoyl) amino] -2-methylpropyl} amino) nicotinic acid Ethyl (1.30 g) was obtained.

(Production Example 242)
MeOH (15.0 mL) and THF (10.0 mL) solution of 5-chloro-6 - {[2- (4-fluorophenoxy) ethyl] amino} nicotinate (1.5 g) and Et ₃ N (0 .68 mL) was added 10% palladium on activated carbon (1.5 g, 50% wet weight). The reaction mixture was stirred at ambient temperature under a hydrogen atmosphere for 6 hours. The catalyst was removed by filtration and the solvent was removed by concentration. To the residue was added a mixture of AcOEt and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE and hexane to give ethyl 6-{[2- (4-fluorophenoxy) ethyl] amino} nicotinate (0.78 g).

(Production Example 243)
(2E) -3- [5-({(1R) -2-[(tert-butoxycarbonyl) amino] -1-methylethyl} amino) pyrazin-2-yl] methyl acrylate (0.96 g) in MeOH To the (4.8 mL) solution was added 4N HCl AcOEt solution (14.3 mL) and the mixture was stirred at ambient temperature for 5 h. After AcOEt (48 mL) was added, the isolated precipitate was collected by filtration to give (2E) -3- (5-{[(1R) -2-amino-1-methylethyl] amino} pyrazin-2-yl) Methyl acrylate dihydrochloride (0.80 g) was obtained.

(Production Example 244)
(2E) -3- [6-({2-[(tert-butoxycarbonyl) amino] ethyl} amino) -5-chloro-3-pyridinyl] ethyl acrylate (3.8 g) in EtOH (38.0 mL) To the solution was added 4N HCl AcOEt solution (25.7 mL) and the mixture was stirred at ambient temperature for 4 h. After IPE (100 mL) was added, the isolated precipitate was collected by filtration and ethyl (2E) -3- {6-[(2-aminoethyl) amino] -5-chloro-3-pyridinyl} acrylate dihydrochloride. Salt (3.2 g) was obtained.

(Production Example 277)
A solution of ethyl 2,6-dichloro-5-fluoronicotinate (820 mg), N- (cyclohexylmethyl) -D-valineamide (914 mg) and Et ₃ N (1.44 mL) in DMA (8.2 mL) at 90 ° C. Stir for 5 hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with 7% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography by high performance liquid chromatography (Yamazen packed high flash column, 26 × 150 mm (silica gel), hexane / AcOEt = 90/10 to 40/60), 2-chloro-6-({(1R) -1- [(Cyclohexylmethyl) carbamoyl] -2-methylpropyl} amino) -5-fluoronicotinic acid ethyl ester (980 mg) was obtained.

(Production Example 278)
Under a nitrogen atmosphere, ethyl 2-chloro-6-({(1R) -1-[(cyclohexylmethyl) carbamoyl] -2-methylpropyl} amino) -5-fluoronicotinate (970 mg), ammonium formate (1. 03 g) and a 10 wt% palladium-supported activated carbon (50% water) (300 mg) in EtOH (19 mL) was refluxed for 45 minutes with stirring. The reaction mixture was filtered, evaporated under reduced pressure and poured into a mixture of AcOEt and water. The separated organic layer was washed with 5% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give 6-({(1R) -1-[(cyclohexylmethyl) carbamoyl] -2-methyl. Propyl} amino) -5-fluoronicotinic acid ethyl ester (910 mg) was obtained.

(Production Example 279)
Ethyl 6-({(1R) -1-[(cyclohexylmethyl) carbamoyl] -2-methylpropyl} amino) -5-fluoronicotinate (300 mg) in THF (2.4 mL) and MeOH (1.2 mL). Dissolved in the mixed solvent. 1M-NaOH aq. (1.58 mL) was added to the solution at ambient temperature. The mixture was stirred at 50 ° C. for 1.5 hours. The reaction mixture was evaporated under reduced pressure and the resulting residue was poured into a mixture of water, AcOEt and THF. 1M-HCl aq. The pH of the aqueous layer was adjusted to about 2. The organic layer is separated, washed with 5% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 6-({(1R) -1-[(cyclohexylmethyl) carbamoyl] -2-methylpropyl}. Amino) -5-fluoronicotinic acid (265 mg) was obtained.

(Production Example 280)
6-({(1R) -1-[(cyclohexylmethyl) carbamoyl] -2-methylpropyl} amino) -5-fluoronicotinic acid (260 mg) and 4-methylmorpholine (0.122 mL) under nitrogen atmospheric pressure To a solution of 1,2-dimethoxyethane (2.6 mL) in water, isobutyl chlorocarbonate (0.12 mL) was added dropwise at <0 ° C. with stirring and the reaction mixture was stirred at <0 ° C. for 30 minutes. Insoluble material was removed by filtration, a suspension of NaBH ₄ (98 mg) in water (2 mL) was added to the filtrate in one portion below 0 ° C. and the mixture was stirred at ambient temperature for 30 minutes. Again a suspension of NaBH ₄ (80 mg) in water (1.5 mL) was added. The reaction mixture was stirred at ambient temperature for 30 minutes and poured into a mixed solution of water, AcOEt and THF. 1M-HCl aq. The pH of the aqueous layer was adjusted to about 2. The organic layer was separated, washed with 10% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography by high performance liquid chromatography (Yamazen packed high flash column, 20 × 65 mm (silica gel), chloroform / MeOH = 94/6 to 88/12), N ^1- (cyclohexylmethyl) -N ^2- [3- Fluoro-5- (hydroxymethyl) pyridin-2-yl] -D-valinamide (255 mg) was obtained.

(Production Example 281)
Activated MnO ₂ (568 mg) in a solution of N ^1- (cyclohexylmethyl) -N ^2- [3-fluoro-5- (hydroxymethyl) pyridin-2-yl] -D-valinamide (245 mg) in AcOEt (5.6 mL). ) Was added at ambient temperature. After stirring at 70 ° C. for 2 hours, activated MnO ₂ (140 mg) was added to the mixture and stirred at 70 ° C. for 1 hour. After cooling, anhydrous magnesium sulfate was added to the reaction mixture and stirred at ambient temperature for 10 minutes. Insoluble material was removed by filtration and washed with AcOEt and chloroform. The filtrate and washings were combined and evaporated under reduced pressure. The resulting residue was evaporated with toluene in vacuo to give a syrup.
Meanwhile, a solution of (diethoxyphosphoryl) ethyl acetate (0.16 mL) in THF (1 mL) was added to a suspension of ice-cooled 60% sodium hydride (33.4 mg) in THF (4 mL), and then the mixture was cooled to ambient temperature. For 15 minutes. The above syrup was added to the mixture at ambient temperature and the reaction mixture was stirred at ambient temperature for 2 hours. The mixture was poured into a mixture of AcOEt and 5% aqueous sodium chloride solution. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography by high performance liquid chromatography (Yamazen packed high flash column, 20 × 65 mm (silica gel), hexane / AcOEt = 86/14 to 34/66), (2E) -3- [6-({(1R) Ethyl-1-[(cyclohexylmethyl) carbamoyl] -2-methylpropyl} amino) -5-fluoropyridin-3-yl] acrylate (247 mg) was obtained.

(Production Example 282)
(2E) -3- [6-({(1R) -1-[(cyclohexylmethyl) carbamoyl] -2-methylpropyl} amino) -5-fluoropyridin-3-yl] ethyl acrylate (240 mg) in MeOH (0.96 mL) and THF (1.92 mL) in a mixed solvent solution were added 1M NaOH aq. (1.18 mL) was added at ambient temperature and the mixture was stirred at 50 ° C. for 1.5 hours. The reaction mixture was washed with 1M HCl aq. Neutralized with (1.18 mL) and evaporated under reduced pressure. The residue was poured into a mixture of AcOEt, THF and 5% aqueous sodium chloride solution. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. To the residue in DMF (3.6 mL) was added O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (104 mg), HOBT (120 mg) and WSCD (138 mg) at ambient temperature and the mixture was added at ambient temperature. Stir for hours. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography by high performance liquid chromatography (Yamazen packed high flash column, 20 × 65 mm (silica gel), hexane / AcOEt = 50/50 to 10/90) to obtain a colorless foamy substance. The resulting foam was triturated with AcOEt and N ^1- (cyclohexylmethyl) -N ^2- (3-fluoro-5-{(1E) -3-oxo-3-[(tetrahydro-2H-pyran-2 -Iyloxy) amino] prop-1-en-1-yl} pyridin-2-yl) -D-valinamide (229 mg) was obtained.

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Table 2: Production Example Number and Chemical Structure Pr: Production Example Number; Str. : Chemical structure

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Table 3: Manufacturing method number and analysis data Pr: Manufacturing method number; Dat. : Analysis data

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Example 1
(2E) -3- {5-Chloro-6-[(2-phenoxyethyl) amino] -3-pyridinyl} -N- (tetrahydro-2H-pyran-2-yloxy) acrylamide (0.70 g) in EtOH ( To the solution was added 2M HCl EtOH solution (2.5 mL) and the mixture was stirred at ambient temperature for 2 hours. AcOEt was added to the reaction mixture, and the isolated precipitate was collected by filtration to give (2E) -3- {5-chloro-6-[(2-phenoxyethyl) amino] -3-pyridinyl} -N-hydroxyacrylamide hydrochloride (0.54 g) was obtained.

  Examples 2, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 28, 29, The compounds disclosed in 30, 31, 32, 34, 35, 36, 37, 38, 39, 40, 45, 46, 47, 48, 52 and 53 were obtained in the same manner as in Example 1.

(Example 3)
4-Chloro-N- {2-[(3-chloro-5-{(1E) -3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy) amino] -1-propen-1-yl } -2-Pyridinyl) amino] ethyl} benzamide (0.45 g) in EtOH (18 mL) was added 2M HCl EtOH solution (1.4 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed by concentration and the residue was triturated with a mixture of EtOH, THF and AcOEt to give 4-chloro-N- [2-({3-chloro-5-[(1E) -3- (hydroxyamino) -3]. -Oxo-1-propen-1-yl] -2-pyridinyl} amino) ethyl] benzamide hydrochloride (0.32 g) was obtained.

  The compounds disclosed in Examples 4 and 10 were obtained in the same manner as in Example 3.

(Example 24)
N ¹ - ^{(cyclohexylmethyl) -N 2 - (5 - {} (1E) -3- oxo-3 - [(tetrahydro -2H- pyran-2-yloxy) amino] prop-1-en-1-yl} pyrazine To a solution of -2-yl) -D-alaninamide (0.46 g) in MeOH (6.9 mL) was added 2 M HCl EtOH solution (1.6 mL) and the mixture was stirred at ambient temperature for 2.5 hours. A solution of AcOEt and IPE was added to the reaction mixture, and the isolated precipitate was collected by filtration to give N ^1- (cyclohexylmethyl) -N ^2- {5-[(1E) -3- (hydroxyamino) -3-oxopropa 1 -En-1-yl] pyrazin-2-yl} -D-alaninamide hydrochloride (0.17 g) was obtained.

  The compounds disclosed in Examples 42, 43, 60, 64, 65, 71, 74 and 96 were obtained in the same manner as in Example 24.

(Example 33)
4-Chloro-N-{(2R) -2-[(5-{(1E) -3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy) amino] prop-1-en-1- To a solution of yl} pyrazin-2-yl) amino] propyl} benzamide (0.42 g) in EtOH (8.4 mL) was added 2M HCl EtOH solution (1.4 mL) and the mixture was stirred at ambient temperature for 3.5 hours. . A solution of AcOEt and ether was added to the reaction mixture, and the isolated precipitate was collected by filtration to give 4-chloro-N-[(2R) -2-({5-[(1E) -3- (hydroxyamino) -3]. -Oxoprop-1-en-1-yl] pyrazin-2-yl} amino) propyl] benzamide hydrochloride (0.31 g) was obtained.

  The compounds disclosed in Examples 41, 44 and 66 were obtained in the same manner as Example 33.

(Example 49)
N ² - (3- chloro -5 - {(1E)-3-oxo-3 - [(tetrahydro -2H- pyran-2-yloxy) amino] prop-1-en-1-yl} pyridin-2-yl To a solution of) -N ^1- (cyclohexylmethyl) -D-alaninamide (0.3 g) in EtOH (3.0 mL) was added 2M HCl EtOH solution (1.3 mL) and the mixture was stirred at ambient temperature for 3 hours. The solvent was removed by concentration and a mixture of AcOEt and water was added to the residue. Saturated sodium bicarbonate aq. The mixture was adjusted to pH 7 with. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE N ² - {3- chloro -5 - [(1E) -3- (hydroxyamino) -3-oxoprop-1-en-1-yl] pyridin-2-yl} -N ¹ -(Cyclohexylmethyl) -D-alaninamide (95 mg) was obtained.

  The compound disclosed in Example 56 was obtained in the same manner as in Example 49.

(Example 50)
(2E) -3- (5-{[(1R) -1-{[benzyl (methyl) amino] methyl} -3-phenylpropyl] amino} pyrazin-2-yl) -N- (tetrahydro-2H-pyran To a solution of -2-yloxy) acrylamide (0.8 g) in EtOH (4 mL) was added 2M HCl EtOH solution (3.1 mL) and the mixture was stirred at ambient temperature for 3 h. AcOEt was added to the reaction mixture, and the separated precipitate was collected by filtration. To the precipitate was added a mixture of AcOEt, THF and water. Saturated sodium bicarbonate aq. The mixture was adjusted to pH 8. The separated organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with IPE to give (2E) -3- (5-{[(1R) -1-{[benzyl (methyl) amino] methyl} -3-phenylpropyl] amino} pyrazin-2-yl) -N. -Hydroxyacrylamide (0.15 g) was obtained.

(Example 51)
(2R) -N- (cyclohexylmethyl) -2-[(5-{(1E) -3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy) amino] prop-1-en-1- To a solution of (Il} pyrazin-2-yl) amino] butanamide (0.8 g) in EtOH (16 mL) was added 2M HCl EtOH solution (2.7 mL) and the mixture was dissolved at ambient temperature for 2.5 hours. The solvent was removed by concentration and a mixture of AcOEt and water was added to the residue. Saturated sodium bicarbonate aq. The mixture was adjusted to pH 5 with. The separated organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with ether to give (2R) -N- (cyclohexylmethyl) -2-({5-[(1E) -3- (hydroxyamino) -3-oxoprop-1-en-1-yl] pyrazine- 2-yl} amino) butanamide (0.45 g) was obtained.

  Examples 54, 55, 57, 58, 59, 61, 62, 63, 68, 69, 70, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, The compounds disclosed in 86, 87, 88, 89, 90, 91, 92, 93, 94 and 95 were obtained in the same manner as in Example 51.

(Example 67)
(2E) -3- [5-({(1R) -2-[(cyclohexylacetyl) amino] -1-methylethyl} amino) pyrazin-2-yl] -N- (tetrahydro-2H-pyran-2- To a solution of (yloxy) acrylamide (0.3 g) in EtOH (6.0 mL) was added 2M HCl EtOH solution (1.0 mL) and the mixture was stirred at ambient temperature for 2.5 hours. The solvent was removed by concentration and a mixture of AcOE and water was added to the residue. Saturated sodium bicarbonate aq. The mixture was adjusted to pH 6 and the isolated precipitate was collected by filtration to give (2E) -3- [5-({(1R) -2-[(cyclohexylacetyl) amino] -1-methylethyl} amino) pyrazine. -2-yl] N-hydroxyacrylamide (0.21 g) was obtained.

(Example 97)
N ^1- (cyclohexylmethyl) -N ^2- (3-fluoro-5-{(1E) -3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy) amino] prop-1-ene-1 To a solution of -yl} pyridin-2-yl) -D-valinamide (220 mg) in EtOH (3.3 mL) was added 2M HCl EtOH (0.92 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours and evaporated under reduced pressure. A mixture of water and AcOEt was added to the residue, and the pH of the aqueous layer was adjusted to about 7 with an aqueous sodium hydrogen carbonate solution. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was triturated with IPE N ¹ - (cyclohexylmethyl) -N ² - {3- fluoro -5 - [(1E) -3- (hydroxyamino) -3-oxoprop-1-en-1-yl ] Pyridin-2-yl} -D-valineamide (120 mg) was obtained.

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Table 4: Example number and chemical structure Ex: Example number; Str. : Chemical structure

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Table 5: Example number and analysis data Ex: Example number; Dat. : Analysis data

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Claims (14)

The following formula (I):

Wherein R ¹ is hydrogen, optionally substituted lower alkyl, cyclo (lower) alkyl, cyclo (higher) alkyl, optionally substituted aryl, optionally substituted heterocyclyl, or aryl-fused cyclo (lower ) Alkyl,
R ² is hydrogen or halogen;
Z is CH or N;
X is

And
R ³ is -OH or lower alkyl optionally substituted with optionally substituted aryl, or lower alkanoyl;
R ⁴ is hydrogen or lower alkyl,
Y is an optionally substituted alkylene)
Or a pharmaceutically acceptable salt thereof. Compounds of formula (I ′)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof. R ¹ is hydrogen, lower alkyl, cyclo (lower) alkyl (lower) alkyl, cyclo (higher) alkyl (lower) alkyl, optionally substituted ar (lower) alkyl, heteroaryl (lower) alkyl, cyclo (lower) Alkyl, cyclo (higher) alkyl, optionally substituted aryl, lower alkylheterocyclyl, aryl-fused cyclo (lower) alkyl,
R ² is hydrogen or halogen;
Z is CH or N;
X is

And
R ³ is lower alkyl optionally substituted with —OH or halogen-substituted aryl, or lower alkanoyl;
R ⁴ is hydrogen or lower alkyl,
The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is hydroxy, aryl, aryl (lower) alkoxy, or lower alkylene optionally substituted with carbamoyl which may be mono- or di-substituted with lower alkyl. Acceptable salt. R ¹ is cyclo (lower) alkyl (lower) alkyl, optionally substituted halogen (ar) alkyl, cyclo (lower) alkyl, cyclo (higher) alkyl, or optionally halogenated aryl,
R ² is hydrogen and Z is N, or R ² is halogen and Z is CH,
X is

And
R ³ is lower alkyl or lower alkanoyl;
R ⁴ is hydrogen or lower alkyl,
4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein Y is lower alkylene. R ¹ is cyclohexylmethyl, benzyl, chlorobenzyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, phenyl, or chlorophenyl;
R ² is hydrogen and Z is N, or R ² is fluorine or chlorine and Z is CH,
X is

And
R ³ is methyl or acetyl,
R ⁴ is hydrogen or methyl,
The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein Y is ethylene, methylmethylene, ethylmethylene, isopropylmethylene, propylene, or isobutylmethylene.   A histone deacetylase inhibitor comprising the compound of claim 1.   Inflammatory disorder, diabetes, diabetic complication, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukemia (APL), organ transplant rejection, autoimmune disease, protozoa, comprising the compound of claim 1 A pharmaceutical composition for treating or preventing infection or tumor.   A pharmaceutical composition comprising a compound according to claim 1 as an active ingredient together with a pharmaceutically acceptable substantially non-toxic carrier or excipient.   2. A compound according to claim 1 intended for use as a medicament.   A method for inhibiting a histone deacetylase comprising the use of a compound according to claim 1.   Use of a compound according to claim 1 for the manufacture of a medicament for inhibiting histone deacetylase.   An inflammatory disorder, diabetes, diabetic complication, homozygous thalassemia, fibrosis, liver cirrhosis, acute promyelocytic leukemia, comprising administering an effective amount of the compound of claim 1 to a human or animal. APL), methods for treating or preventing organ transplant rejection, autoimmune diseases, protozoan infections or tumors.   To treat or prevent inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukemia (APL), organ transplant rejection, autoimmune diseases, protozoal infections or tumors Use of a compound according to claim 1 for the manufacture of a medicament.   A pharmaceutical composition according to claim 1 and a document relating thereto (the document comprising said pharmaceutical composition comprising inflammatory disorder, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukemia) (APL), a commercial package containing organ transplant rejection, autoimmune disease, protozoal infection or that can or should be used to treat or prevent tumors).